CN107129514B - erythromycin A ketolide antibiotic derivative, and preparation method and application thereof - Google Patents
erythromycin A ketolide antibiotic derivative, and preparation method and application thereof Download PDFInfo
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- CN107129514B CN107129514B CN201610118615.3A CN201610118615A CN107129514B CN 107129514 B CN107129514 B CN 107129514B CN 201610118615 A CN201610118615 A CN 201610118615A CN 107129514 B CN107129514 B CN 107129514B
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- erythromycin
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
The invention discloses a series of erythromycin A ketolide antibiotic derivatives containing substituted quinoline or isoquinoline, as shown in formula I, a preparation method and application thereof, and side chain intermediates and a synthesis method of each compound. The key points of the invention are as follows: the compound shown in the formula I has the drug effect of broad-spectrum antibiotics and simultaneously inhibits the outstanding antibacterial activity and the anti-drug-resistance activity of gram-positive bacteria and gram-negative bacteria. The compound provided by the invention can be used as a broad-spectrum antibiotic, and has antibacterial and antiviral activities for simultaneously inhibiting gram-positive bacteria and gram-negative bacteria.
Description
Technical Field
The invention belongs to the technical field of medicines. The invention relates to a series of erythromycin A ketolide antibiotic derivatives with high antibacterial activity and containing substituted quinoline or isoquinoline rings, a synthetic method thereof, a related intermediate synthetic method, biological activity of the compounds and application of the compounds as broad-spectrum antibiotics in inhibiting gram-positive bacteria and gram-negative bacteria and resisting viruses.
Compared with the prior art
bacterial resistance has become a serious problem in the world's field of anti-infective therapy. Bacterial resistance and infection with resistant bacteria are great challenges facing the field of infection resistance in the 21 st century. With the increasing use of antibiotics, the problem of drug resistance is becoming more serious, which results in failure of anti-infective therapy, resulting in increased morbidity and mortality, and increased medical costs. And in recent years, the phenomenon of hepatotoxicity of telithromycin is reported, so that the clinical application range of telithromycin is limited.
Therefore, there is a need to accelerate the research of novel antibiotics with broad-spectrum antibacterial activity, especially to enhance the action of macrocyclic ketolide antibiotic drugs on gram-negative bacteria and reduce the toxic and side effects of the drugs such as hepatotoxicity. The compound with novel chemical structure is designed and screened, the inhibitory activity to macrolide drug-resistant bacteria is improved, the induced drug resistance of the drug to bacterial strains is reduced and avoided, the problem of multiple drug resistance is solved, and a safer and more effective drug is provided for clinic.
At present, much work is carried out on structural modification research of macrocyclic ketolide, a series of macrocyclic ketolide derivatives containing sulfur aryl alkyl side chains at 11, 12-positions are designed and synthesized by the schottoman et al, and in-vitro activity tests are carried out, wherein some compounds show good activity to macrolide drug-resistant and sensitive bacteria. The activity of 9n and 9k was superior to telithromycin in terms of pyogenes, erythromycin-sensitive streptococcus pneumoniae, erythromycin-sensitive haemophilus influenzae, which are sensitive and resistant to erythromycin, and the antimicrobial spectrum of 9a, 9e, 9k and 9n (formula below) was similar to that of telithromycin.
Macrocyclic ketolide derivatives with sulfur-containing arylalkyl side chain in the 11, 12-position
Based on the successful development of the quinorubicin, the Abbott laboratory continues to make an intensive structural modification of the 6-position of the macrolide. They synthesized a series of macrocyclic ketolide derivatives 9 with 6-propargyl aromatic heterocyclic side chains. It has been found that the activity of the compounds is best when the aromatic heterocyclic moiety is a biaryl ring. When telithromycin was used as a control, compounds 9d and 9e (shown below) were highly active against erythromycin resistance induced by erm and mef genes. The bacteriostatic activity of the compound 9d and 9e on the streptococcus pneumoniae 5979 containing erm genes is 100 times higher than that of telithromycin. Such compounds provide new candidates for drug-resistant macrolide antibiotics.
Macrocyclic ketolide derivatives with 6-propargyl aromatic heterocyclic side chain
The subject group Chen Shizhuo et al synthesized a series of 5-dimethylamino sugar 4 '-O derivatives, and research showed that the introduction of hydroxyl at the 4' position of 5-dimethylamino sugar is beneficial to improving the antibacterial activity against penicillin-sensitive bacteria and drug-resistant bacteria. Compared with telithromycin, it retains antibacterial activity against all penicillin-sensitive bacteria and other drug-resistant bacteria, and retains the same activity as telithromycin with respect to erythromycin-sensitive ESSP bacteria and ESSPy bacteria.
the structure-activity relationship shows that the dimethylamino sugar is combined with 23S rRNA of the V region through a hydrogen bond to play a pharmacodynamic effect. The 4' -OH group of the dimethylamino sugar provides another hydrogen bond donor to bind to the amino acid residue of the binding domain and thus compound 26 (formula below) has superior antibacterial activity to erythromycin and clarithromycin. Whereas the introduction of hydrophobic groups such as alkyl, aryl groups at the 4' position does not enhance the antibacterial activity due to the inability of the macrolide to interact with the ribosomal subunit (e.g. 25 and 29).
5-dimethylamino sugar 4' -OH modified macrocyclic ketolide derivatives
The compound of the application is a macrocyclic ketolide derivative with substituted quinoline or isoquinolyl and special side chain linkage mode at 11, 12-positions, and is subjected to in vitro antibacterial activity test. The method has the advantages of simple and efficient synthesis, and the target product is obtained by taking commercial quinoline or isoquinoline substitute as a starting material through simple reaction and high yield. Meanwhile, the antibacterial activity is outstanding, some compounds show good activity to sensitive bacteria in large ring and ester resistance, the whole antibacterial activity is equivalent to the activity level of telithromycin, and even the antibacterial level to some strains exceeds the activity level of telithromycin; some compounds show outstanding antibacterial activity to drug-resistant bacteria, the antibacterial level exceeds telithromycin by one to two orders of magnitude, and the problem of drug-resistant bacteria is expected to be solved.
Macrocyclic ketolide derivatives containing double-bond side chain substituted quinoline at 11, 12-position
disclosure of Invention
The invention aims to provide macrocyclic ketolide compounds with broad-spectrum antibacterial activity, namely erythromycin A macrocyclic ketolide antibiotic derivatives with a new structure and pharmaceutically acceptable salts thereof, and provides a preparation method, a pharmaceutical composition and application thereof in preparation of antibacterial or viral medicaments.
In order to solve the technical problem, the invention provides the following technical scheme:
The first aspect of the technical scheme of the invention provides macrocyclic ketolide antibiotic compounds shown as a formula I and pharmaceutically acceptable salts thereof, wherein the macrocyclic ketolide antibiotic compounds have the following structural formula:
Wherein X-Y is selected from CH ═ CH or O-CH2，
Q is selected from substituted or unsubstituted quinoline or isoquinoline, wherein the substituent is selected from H, C1-6 alkyl, C1-6 alkoxy, C6-10 aryl, benzyloxy,
R is H atom or fluorine atom.
Preferred compounds are represented by formula IA, characterized in that,
Wherein X-Y is selected from CH ═ CH or O-CH2，
R1Selected from C1-6 alkyl, C1-6 alkoxy, C6-10 aryl and benzyloxy;
R is selected from fluorine atom or H.
In formula IA, R is preferred1The position is at the 6-or 7-position of the quinoline ring.
preferred compounds are represented by formula IB, wherein,
Wherein X-Y is selected from CH ═ CH or O-CH2，
R2Selected from H, C1-6 alkyl, C1-6 alkoxy, C6-10 aryl and benzyloxy;
R2Selected from fluorine atoms or H.
preferred compounds are represented by formula IC, characterized in that,
Wherein X-Y is selected from CH ═ CH or O-CH2，
R3Selected from H, C1-6 alkyl, C1-6 alkoxy, C6-10 aryl and benzyloxy; r3Selected from fluorine atoms or H.
C1-6 alkyl, C1-6 alkoxy, C6-10 aryl,
The C1-6 alkyl group of the present invention may be a C1-6 straight or branched chain alkyl group, and the C1-6 alkoxy group is a C1-6 straight or branched chain alkyl group further linked to an oxygen atom. Among C1-6 linear or branched alkyl groups, preferred is C1-5 linear or branched alkyl group or C2-6 linear or branched alkyl group; still more preferred is C1-4 straight or branched chain alkyl, C2-5 straight or branched chain alkyl or C3-6 straight or branched chain alkyl; more preferred is C1-3 straight or branched chain alkyl, C2-4 straight or branched chain alkyl, C3-5 straight or branched chain alkyl, or C4-6 straight or branched chain alkyl; further preferred are C1-2 linear or branched alkyl groups, C2-3 linear or branched alkyl groups, C3-4 linear or branched alkyl groups, C4-5 linear or branched alkyl groups, C5-6 linear or branched alkyl groups. More preferred C1-6 straight or branched chain alkyl groups are selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, pentyl, isopentyl. More preferred C1-4 straight or branched chain alkyl groups are selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl.
Preferred C6-10 aryl groups are selected from
Preferred compounds are specifically listed below:
(S1)11, 12-dideoxy-3-O-decladinose-6-O-methyl-3-oxo-12, 11- (oxycarbonyl (4-isoquinolinyl-3 (E) -butenyl) imino) erythromycin
(S2)11, 12-dideoxy-3-O-descladinose-6-O-methyl-3-oxo-12, 11- (oxycarbonyl (quinoline-7-hydroxy substituted propyl) imino) erythromycin
(S3)11, 12-dideoxy-3-O-decladinose-6-O-methyl-3-oxo-12, 11- (oxycarbonyl (3- (6-methyl-quinolyl) -3(E) -butenyl) imino) erythromycin
(S4)11, 12-dideoxy-3-O-decladinose-6-O-methyl-3-oxo-12, 11- (oxycarbonyl (3- (6-methoxy-quinolyl) -3(E) -butenyl) imino) erythromycin
(S5)11, 12-dideoxy-3-O-decladinose-6-O-methyl-3-oxo-12, 11- (oxycarbonyl (3- (6-benzyloxy-quinolinyl) -3(E) -butenyl) imino) erythromycin
(S6)11, 12-dideoxy-3-O-decladinose-6-O-methyl-3-oxo-12, 11- (oxycarbonyl (3- (6-phenyl-quinolyl) -3(E) -butenyl) imino) erythromycin
(S7)11, 12-dideoxy-3-O-decladinose-6-O-methyl-3-oxo-12, 11- (oxycarbonyl (3- (7-methyl-quinolyl) -3(E) -butenyl) imino) erythromycin
(S8)11, 12-dideoxy-3-O-decladinose-6-O-methyl-3-oxo-12, 11- (oxycarbonyl (3- (7-methoxy-quinolinyl) -3(E) -butenyl) imino) erythromycin
(S9)11, 12-dideoxy-3-O-decladinose-6-O-methyl-3-oxo-12, 11- (oxycarbonyl (3- (7-benzyloxy-quinolinyl) -3(E) -butenyl) imino) erythromycin
(S10)11, 12-dideoxy-2-fluoro-3-O-decladinose-6-O-methyl-3-oxo-12, 11- (oxycarbonyl (3-quinolyl-3 (E) -butenyl) imino) erythromycin
(S11)11, 12-dideoxy-2-fluoro-3-O-descladinose-6-O-methyl-3-oxo-12, 11- (oxycarbonyl (quinoline-3-hydroxy-substituted propyl) imino) erythromycin
The second aspect of the technical scheme of the invention is to provide a preparation method of the macrocyclic ketolide antibiotic derivative with the novel structure in the first aspect. Wherein the starting material is clarithromycin, and a proper intermediate is obtained by adopting a reaction method reported by a literature or feasible in synthetic chemistry and is used as the raw material of the invention, and the structural formula is as follows:
Wherein Ac is acetyl.
The reaction formula of the process of the present invention for starting material 6 is as follows:
Wherein, the (CH)3CO)2Is acetic anhydride, ClCO2CCl3Is trichloromethyl chloroformate, (COCl)2is oxalyl chloride, DBU is 1, 8-diazabicycloundecen-7-ene, DMSO is dimethyl sulfoxide, CDI is carbonyldiimidazole, DMF is N, N-dimethylformamide, and Ac is acetyl.
The synthesis of the compounds of the invention comprises the addition reaction of a suitably protected macrolide intermediate compound 6 with a preselected primary amine side chain containing a quinoline or isoquinoline ring; or the 2 '-hydroxyl is protected, and then the 2-position of the large ring is substituted and then the 2' -hydroxyl protecting group is removed.
the method comprises the following steps:
1, introducing substituted quinoline or isoquinoline ring-substituted carbamate functional groups at 11 and 12-positions of the raw material 6 to obtain a corresponding substituted erythromycin A quinoline or isoquinoline ring-side chain ketolide derivative;
2, protecting the 2' -position of the ketolide derivative, then substituting the 2-position and then deprotecting to obtain the corresponding 2-position substituted erythromycin A quinoline or isoquinoline ring side chain ketolide derivative.
wherein X, Y, Q, R is defined as the first aspect of the present invention.
The macrocyclic ketolide compounds of the present invention with novel structure can be prepared by starting from clarithromycin and using known literature reports or synthetic chemistry methods which are publicly known and feasible to obtain suitable derivatives as the starting material of the present invention, such as starting compound 6, and using the methods reported in J.Med.chem,41,4080-4100, 1998.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising at least one compound of the quinoline or isoquinoline substituent erythromycin A ketolide antibiotic derivatives of the first aspect and a pharmaceutically acceptable carrier. The pharmaceutical composition may be prepared according to methods well known in the art. The compounds of the invention may be formulated into any dosage form suitable for human or animal use by combining them with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The compounds of the present invention are generally present in the pharmaceutical compositions in an amount of from 0.1 to 95% by weight.
the compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by enteral or parenteral routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oromucosal, ophthalmic, pulmonary and respiratory, dermal, vaginal, rectal, and the like.
The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.
The compound can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle drug delivery systems.
For tableting the compounds of the invention, a wide variety of excipients known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, carboxymethyl cellulose sodium, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.
The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
To encapsulate the administration units, the active ingredient of the compounds of the invention can be mixed with diluents and glidants and the mixture can be placed directly into hard or soft capsules. Or the effective component of the compound of the invention can be prepared into granules or pellets with diluent, adhesive and disintegrating agent, and then placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants, glidants used to prepare the compound tablets of the present invention may also be used to prepare capsules of the compound of the present invention.
In order to prepare the compound of the invention into injection, water, ethanol, isopropanol, propylene glycol or a mixture thereof can be used as a solvent, and a proper amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator which are commonly used in the field can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol and glucose can be added as proppant for preparing lyophilized powder for injection.
In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.
for the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.
The dosage of the pharmaceutical composition of the compound of the present invention to be administered may vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route and dosage form of administration, and the like. Generally, a suitable daily dosage range for a compound of the invention is from 0.001 to 150mg/Kg body weight, preferably from 0.1 to 100mg/Kg body weight, more preferably from 1 to 60mg/Kg body weight, and most preferably from 2 to 30mg/Kg body weight. The above-described dosage may be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention is used in combination with other therapeutic agents, its dosage should be adjusted according to the actual situation.
According to a fourth aspect of the present invention there is provided the use of a compound according to the first aspect of the present invention in the manufacture of a medicament for inhibiting bacteria.
The bacterial strain comprises gram-positive bacteria and gram-negative bacteria. Wherein the gram-positive bacteria include Staphylococcus, Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus epidermidis; gram-negative bacteria include Moraxella catarrhalis, Haemophilus influenzae; and other pathogens such as Rickettsia, Mycoplasma pneumoniae, Chlamydia, Roman pathogen, bird blood plasma, Toxoplasma, Mycobacterium, Listeria monocytogenes, meningococcus.
Advantageous technical effects
The antibiotic derivatives of the macrolide compound erythromycin A containing the substituted quinoline ring derivatives or isoquinoline ring substituted side chains in the invention have the in vitro antibacterial activity reaching the level equivalent to that of telithromycin, and are superior to telithromycin for part of strains, and the sample compounds designed and synthesized by the invention avoid the side chain structure which can cause hepatotoxicity; compared with telithromycin synthesis, the sample compound related by the invention has the advantages of short synthetic route, simple operation, high total yield and low cost. Therefore, the drug candidate with novel structure, strong activity and simple synthesis is provided, and the drug candidate can be used as a broad-spectrum antibiotic to inhibit gram-positive bacteria and gram-negative bacteria and resist viruses.
Detailed Description
the present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention. The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible.
For all of the following examples, standard procedures and purification methods known to those skilled in the art may be used. Unless otherwise indicated, all temperatures are expressed in degrees Celsius. The structure of the compounds is determined by nuclear magnetic resonance spectroscopy (NMR) and/or Mass Spectrometry (MS).
Preparation example section
The structure of the compound is shown by nuclear magnetic resonance hydrogen spectrum (1H NMR), nuclear magnetic resonance carbon spectrum (C13C NMR) and Mass Spectrometry (MS). The hydrogen and carbon spectral shifts (δ) for nuclear magnetic resonance are given in parts per million (ppm). NMR spectra were obtained using a NMR spectrometer model Mercury-300, Mercury-400, Bruke-400 or Mercury-600, deuterated chloroform (CDCl)3) Or heavy water (D)2O) or deuterated dimethyl sulfoxide (DMSO-d)6) As solvent Tetramethylsilane (TMS) was used as internal standard.
The high resolution mass spectrum is measured by an Agilent 1100series LC/MSD trap mass spectrometer or a Theromo active orbitrap plus LC/MSD mass spectrometer.
the column chromatography generally uses 160-200 mesh silica gel as a carrier.
The anhydrous solvents were all processed by standard methods. Other reagents were all commercially available analytical grade.
Wherein,
preparation example 1
Synthetic route of Scheme 1 intermediate side chain a2
Scheme 1 reagent and reaction conditions a.2- (but-3-en-1-yl) isoindoline-1,3-dione, Pd (dba)2,PPh3,Na2CO3,DMF,120℃；b.NH2NH2.H2O,EtOH,reflux,80℃。
4-bromoisoquinoline (0.21g,1.0mmol), 4-phthalimido-1-butene (0.20g,1.0mmol), triphenylphosphine (21mg, 8%) and sodium carbonate (0.21g,2.0mmol) were dispersed in 4 ml of DMF under protection of argon, Pd (dba) was added2(23mg, 4%). The reaction was heated to 120 ℃ and stirred overnight. The reaction mixture was cooled to room temperature, diluted with 50ml of ethyl acetate, washed with 50ml of saturated brine 5 times, dried over anhydrous sodium sulfate, and spin-dried. The residue was isolated by column chromatography (1/4 petroleum ether/ethyl acetate) to give intermediate a1(0.38 g).
Intermediate a1 prepared in the above step was dispersed in 5ml of ethanol, and hydrazine hydrate (2eq) was added thereto, and heated under reflux for 4 hours, and a large amount of solid was eluted. Filtration, spin-drying of the filtrate, dissolution and dispersion of the residue in 30ml of dichloromethane, removal of the insoluble material and spin-drying gave intermediate a2, which was used directly in the next step.
Preparation example 2
Synthetic route of Scheme 2 intermediate b2
scheme 2 reagent and reaction conditions a.N- (3-Bromopropyl) naphthalimide, K2CO3,DMF,90℃；b.NH2NH2.H2O,EtOH,reflux,80℃。
7-Hydroxyquinoline (2.0g, 13.8mmol), N- (3-bromopropyl) phthalimide (3.7g, 13.8mmol) and potassium carbonate (2.1g, 15.2mmol) were added to N, N-dimethylformamide (40ml), respectively, and the mixture was heated to 90 ℃ to react for 10 hours. TLC (ethyl acetate/petroleum ether 1:3) showed the reaction was complete. The reaction was stopped, the reaction solution was cooled to room temperature, filtered to remove solids, the filtrate was concentrated, the residue was dissolved in dichloromethane, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and subjected to silica gel column chromatography (ethyl acetate/petroleum ether 1:15) to give a pale yellow compound 1b (4.186g, yield 91.6%).
Compound 2b (1.5g,4.5mmol) was dispersed in 30ml of anhydrous ethanol, 85% hydrazine hydrate (2eq) was added dropwise to the reaction solution, heated to 80 ℃ and refluxed for 5 hours, and TLC (methanol/chloroform 1:10) showed completion of the reaction. Concentrating the reaction solution under reduced pressure to obtain light yellow solid, extracting with chloroform, washing the organic phase with 2mol/L sodium hydroxide solution, washing with water, washing with saturated salt solution, drying with anhydrous sodium sulfate, filtering, and concentrating the organic phase to obtain 0.728g of light yellow oily compound, which is directly used in the next step without separation.
Preparation examples 3 to 9
Synthetic route of Scheme 3 intermediate c3-i3
scheme 1 reagent and reaction conditions a.Br2，Py,CCl4,reflux,4h；b.
2-(but-3-en-1-yl)isoindoline-1,3-dione,Pd(dba)2,PPh3,NaOAc,DMF,120℃,16h；c.NH2NH2.H2O,EtOH,reflux,4h。
The corresponding quinoline derivative (1eq) was dissolved in carbon tetrachloride (1g/10ml) and bromine (1.1eq) was added at room temperature. After the reaction mixture was refluxed by heating, pyridine (1.2eq) was added dropwise, and the reflux by heating was continued for 4 hours. Cooling the reaction solution to room temperature, adding dichloromethane to dilute the reaction solution, washing with saturated salt solution for 3 times, drying with anhydrous sodium sulfate, filtering, and spin-drying. The residue was separated by column chromatography to give the corresponding intermediate c1-i1.
Intermediate c1-i1(1eq), 4-phthalimido-1-butene (1eq), triphenylphosphine (8%) and sodium acetate (2eq) were dispersed in DMF under argon protection with addition of Pd (dba)2(4%). The reaction was heated to 120 ℃ and stirred overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with saturated brine 5 times, dried over anhydrous sodium sulfate, and spin-dried. The residue was isolated by column chromatography to give intermediate c2-i 2.
The intermediate c2-i2 prepared in the previous step was dispersed in ethanol, hydrazine hydrate (2eq) was added, and heated under reflux for 4 hours, and a large amount of solid was eluted. Filtration, spin-drying of the filtrate, dissolution and dispersion of the residue in 30ml of dichloromethane, removal of the insoluble material and spin-drying gave intermediate c3-i3, which was used directly in the next step.
Preparation example 10 preparation of starting Compound 6
The macrocyclic ketolide compounds of the present invention with novel structure can be prepared by starting from clarithromycin and using known literature reports or synthetic chemistry methods which are publicly known and feasible to obtain suitable derivatives as the starting material of the present invention, such as starting compound 6, and using the methods reported in J.Med.chem,41,4080-4100, 1998.
clarithromycin (50g, 66.9mmol) was dispersed in 350ml of water, and 1mol/L hydrochloric acid (350ml) was added thereto, followed by stirring at room temperature, whereby the reaction mixture became gradually viscous. The reaction was continued for 3h, the reaction gradually became clear and the reaction was complete by TLC (chloroform/methanol 10: 1). Adjusting pH to 9-10 with 2mol/L sodium hydroxide solution to obtain a large amount of white solid, extracting the product with dichloromethane for several times, combining organic phases, washing with saturated salt water, and drying with anhydrous sodium sulfate. Concentration under reduced pressure, dichloromethane/methanol 50:1) column chromatography under reduced pressure gave pure product (1)37.9g, 96% yield.
1H NMR(300MHz,CDCl3):δ5.172(dd,1H,J＝2.1Hz,J＝10.8Hz),4.386(d,1H,J＝7.2Hz),3.917(s,1H),3.851(s,1H),3.681(s,1H),2.965(s,3H),2.262(s,6H),2.114(q,1H,J＝7.5Hz),1.362(s,3H),1.178(s,3H),0.831(t,3H,J＝7.2Hz).
13C NMR(75MHz,CDCl3):221.116,175.416,107.026,88.749,79.391,78.450,74.604,71.065,70.685,70.184,66.087,49.978,45.936,44.976,40.666,39.153,37.932,36.281,28.452,21.842,21.676,19.178,18.152,16.606,15.606,13.051,10.839,8.644.
HR-MS(ESI)(M+H)+m/z 590.3885, calculated: c30H56NO10590.3898.
After the compound 1(24.32g,41.29mmol) is taken up in water by toluene, dissolved in 300ml of dry dichloromethane, protected by argon, cooled by an ice-water bath, and completely dissolved, triethylamine (6.9ml,49.55mmol) and acetic anhydride (4.67ml,49.55mmol) are added dropwise at 0 ℃. After stirring at room temperature for 10 hours, the reaction was completed by detection with TCL (chloroform/methanol 10/1), 100ml of ice water was added to the reaction mixture to terminate the reaction, the mixture was allowed to stand for liquid separation, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give 27.38g of a crude pale yellow foamy product, which was subjected to separation and purification by silica gel column chromatography under reduced pressure (dichloromethane/methanol/triethylamine 30:1: 2%) to give 2(21.9g, 84%) of a white foamy solid 2.
1H NMR(300MHz,CDCl3):δ5.158(dd,1H,J＝2.1Hz,J＝10.8Hz),4.742(dd,1H,J＝7.8Hz,J＝10.5Hz),4.592(d,1H,J＝7.5Hz),3.945(s,1H),3.807(s,1H),3.705(d,1H,J＝2.4Hz),3.459(m,2H),3.250(s,1H),2.930(s,3H),2.245(s,6H),2.031(s,3H),0.927(d,3H,J＝7.8Hz),0.819(t,3H,J＝7.2Hz).
13C NMR(75MHz,CDCl3):221.376,175.066,170.355,100.024,81.446,78.379,78.187,77.192,74.561,71.914,70.021,69.222,63.544,50.126,45.877,44.418,41.013,38.880,41.013,38.880,37.688,36.086,31.455,21.795,21.532,19.658,18.329,17.767,16.585,15.714,13.002,10.852,8.233.
HR-MS(ESI)(M+H)+m/z 632.4018, calculated: c32H58NO11632.4010.
Compound 2(1.94g,3.07mmol) was thoroughly hydrated with toluene and dissolved in 20ml of dry dichloromethane, pyridine (3.97ml,49.07mmol) was added, under argon protection, and thoroughly mixed for 0.5h with cooling in an ice-water bath. A solution of trichloromethyl chloroformate (0.96ml,7.973mmol) in methylene chloride (3ml) was added dropwise to the system. The reaction solution immediately turns light yellow, the reaction is continued at room temperature, the reaction solution is gradually turbid and the color is deepened, and TLC (acetone/petroleum ether/triethylamine 1.5:1: 1%) after 24h shows that the reaction is complete. A small amount of crushed ice was added to the system to terminate the reaction, and a large amount of methylene chloride was added to completely dissolve the solid in the system. Saturated sodium bicarbonate solution is carefully added, the mixture is stirred at normal temperature, liquid is separated after no bubbles are generated, the organic phase is washed by half-saturated sodium chloride and saturated sodium chloride respectively, the organic phase is dried by anhydrous sodium sulfate and is concentrated under reduced pressure, and the mixture is subjected to column chromatography under reduced pressure (petroleum ether/acetone/triethylamine 2.5:1:0.5 percent) to obtain a light yellow product 3(1.51g, 75 percent).
1H NMR(300MHz,CDCl3):δ5.122(d,1H,J＝9.0Hz),4.714～4.774(m,2H),4.578(d,1H,J＝7.5Hz),3.690(s,1H),3.452～3.507(m,2H),2.914(s,3H),2.640～2.746(m,2H),2.549～2.604(m,1H),2.250(s,6H),2.057(s,3H),1.489(s,3H),1.180(d,3H,J＝6.6Hz),1.139(d,3H,J＝7.5Hz),0.937(d,3H,J＝7.2Hz),0.861(t,3H,J＝7.5Hz).
13C NMR(75MHz,CDCl3):212.527,175.288,170.271,154.452,100.302,85.252,81.591,81.284,78.523,78.158,75.655,71.920,69.315,63.592,50.009,45.650,44.540,41.079,38.969,37.824,36.304,31.359,22.513,21.862,21.524,19.676,18.702,15.630,14.513,13.436,10.520,8.153.
HR-MS(ESI)(M+H)+m/z 658.3815, calculated: c33H56NO12658.3797.
Oxalyl chloride (0.82g,6.48mmol) was dissolved in dry dichloromethane (15ml), cooled to-78 ℃ under argon, in an acetone-dry ice bath, after stabilization, a solution of DMSO (1.01g,12.96mmol) in dichloromethane (2ml) was added dropwise, after stabilization, a well dried solution of compound 3(2.84g,4.32mmol) in dichloromethane (25ml) was added dropwise, and the reaction was maintained at-78 ℃ for 4 h. A solution of triethylamine (2.62g,25.93mmol) in dichloromethane (2ml) was added dropwise and the reaction was gradually warmed to room temperature, TLC (chloroform/methanol 10:1) showed that the reaction was substantially complete. Diluting with dichloromethane, washing with 1N hydrochloric acid, saturated sodium bicarbonate, and saturated salt, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain yellowish foamy solid, and performing column chromatography (acetone/petroleum ether 3:1) under reduced pressure to obtain pure product 4(1.98g, 70%) in the form of white foam.
1H NMR(300MHz,CDCl3):δ5.054(dd,1H,J＝2.7Hz,J＝9.9Hz),4.732(dd,1H,J＝10.2Hz,J＝8.1Hz),4.623(s,1H),4.377(d,1H,J＝7.8Hz),4.160(d,1H,J＝7.5Hz),3.781(q,1H,J＝6.9Hz),3.543(m,1H),2.941～3.026(m,2H),2.645(s,3H),2.241(s,6H),2.044(s,3H),1.942(s,1H),1.813～1.866(m,1H),1.705～1.736(m,1H),1.540(s,3H),1.472(s,3H),1.401～1.424(m,3H),1.344～1.361(m,3H),1.315(s,3H),1.229～1.265(m,3H),1.129～1.154(m,6H),0.894(t,3H,J＝7.5Hz).
13C NMR(75MHz,CDCl3):213.277,204.412,170.193,169.492,154.295,101.870,84.890,81.311,78.767,78.571,77.126,72.009,69.600,63.847,51.529,49.963,47.979,44.222,41.082,39.674,38.523,30.859,22.780,21.834,21.421,20.105,18.312,16.612,14.526,13.971,12.904,10.774.
HR-MS(ESI)(M+H)+m/z 656.3627,calcd for C33H54NO12656.3641.
Fully dried compound 4(11.48g,17.5mmol) was dissolved in 150ml dry acetone, under argon, DBU (3.92ml,26.25mmol) was added dropwise, heated under reflux for 4h, and TLC (chloroform/methanol 10:1) showed complete reaction. 5% monopotassium phosphate solution is added dropwise to adjust the pH to be neutral. After distilling off part of the acetone under reduced pressure, diluting with a large amount of dichloromethane solution, washing with saturated saline, drying over anhydrous sodium sulfate, concentrating under reduced pressure, and recrystallizing the crude product with ethyl acetate to obtain pure white solid 5(8.0g, 75%).
1H NMR(300MHz,CDCl3):δ6.597(s,1H),4.987(d,1H,J＝9.6Hz),4.719(t,J＝8.0Hz1H),4.348(d,1H,J＝8.0Hz),4.130(d,1H,J＝8.0Hz),3.724(q,1H,J＝6.8Hz),3.504～3.544(m,1H),3.165(q,1H,J＝6.0Hz),3.032～3.070(m,1H),2.861(s,3H),2.637(t,1H,J＝8.8Hz),2.237(s,6H),2.015(s,3H),2.034(s,3H),1.942(s,1H),1.813～1.866(m,1H),1.705～1.736(m,1H),1.544～1.595(m,3H),1.472(s,3H),1.344～1.361(m,3H),1.325(s,3H),1.229～1.265(m,3H),1.113～1.159(m,6H),0.929(t,3H,J＝7.2Hz).
13C NMR(100MHz,CDCl3):207.404,170.143,170.109,142.441,139.167,102.170,81.691,81.326,78.676,73.741,71.914,69.478,63.926,51.583,50.770,47.503,41.027,40.522,38.811,30.759,22.791,22.354,21.759,21.380,19.287,15.166,14.396,13.940,11.313.
HR-MS(ESI)(M+H)+m/z 612.3755, calculated: c32H54NO10612.3742.
70% NaH (0.66g,19.31mmol) was dispersed in 60ml dry DMF and cryotank cooled to-15 deg.C under argon. Compound 5(5.90g,9.66mmol) was added portionwise and after thorough mixing a solution of CDI (4.69g,28.967mmol) in DMF (40ml) was added dropwise. The reaction was continued for 2h at low temperature and TLC (acetone/petroleum ether 1.5:1) showed completion of the reaction. Pouring the reaction solution on 150ml of ice, standing, precipitating a large amount of foam white solid, performing suction filtration, and washing with water to obtain the white solid. This solid was dissolved in methylene chloride solution, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and subjected to column chromatography using petroleum ether/acetone (3:1) under reduced pressure to obtain a white foamy solid 6(5.4g, 80%).
1H NMR(400MHz,CDCl3):δ8.076(s,1H),7.358(s,1H),7.056(s,1H),6.783(s,1H),5.675(dd,1H,J＝9.6Hz,J＝2.4Hz),4.702(t,1H,J＝8.0Hz),4.332(d,1H,J＝7.6Hz),4.109(d,1H,J＝8.8Hz),3.730(q,1H,J＝6.8Hz),3.457～3.497(m,1H),3.142(d,1H,J＝6.4Hz),3.018(t,3H,J＝6.0Hz),2.769(s,3H),2.624(t,1H,J＝8.8Hz),2.244(s,6H),2.024(s,3H),1.817～1.849(m,6H),1.605～1.726(m,3H),1.412～1.430(m,3H),1.340～1.357(m,3H),1.390(s,3H),1.198～1.229(m,3H),0.934(t,3H,J＝7.2Hz).
13C NMR(100MHz,CDCl3):205.259,169.983,169.129,146.225,138.421,137.323,131.193,117.380,102.226,84.815,81.232,78.826,71.815,69.425,63.355,53.707,51.309,50.542,47.683,40.912,40.565,39.220,30.550,22.926,21.656,21.218,20.974,20.444,19.190,15.331,14.294,13.540,10.745.
HR-MS(ESI)(M+H)+m/z 706.3895, calculated: c33H58N2O14706.3883.
Examples section
Example 1
(S1) preparation of 11, 12-dideoxy-3-O-decladinose-6-O-methyl-3-oxo-12, 11- (oxycarbonyl (4-isoquinolinyl-3 (E) -butenyl) imino) erythromycin
Synthetic route to compound S1:
Intermediate 6(0.71g, 1eq) and intermediate (a2, 4eq) were dissolved in 10mL of a mixed system of acetonitrile/water (9:1) and heated under reflux overnight. The reaction mixture was cooled to room temperature, diluted with dichloromethane, and washed with saturated brine 3 times. The organic phase was dried over anhydrous sodium sulfate, filtered and spin dried. The residue was separated by column chromatography to give the desired compound S1.1H NMR(400MHz,CDCl3)δ9.10(s,1H),8.57(s,1H),8.11(d,J＝8.4Hz,1H),8.01–7.85(m,2H),7.68(dd,J＝17.3,9.7Hz,2H),7.56(dd,J＝17.9,10.5Hz,1H),7.15(d,J＝15.7Hz,1H),6.33(tt,J＝15.2,7.6Hz,1H),4.99(d,J＝9.4Hz,1H),4.97–4.81(m,1H),4.35(d,J＝7.1Hz,2H),4.24(d,J＝8.5Hz,1H),4.23–4.05(m,3H),3.91(dd,J＝16.1,10.7Hz,2H),3.88–3.76(m,3H),3.74–3.62(m,2H),3.62–3.51(m,2H),3.45–3.29(m,2H),3.23–3.01(m,4H),2.94(dd,J＝12.3,7.8Hz,2H),2.74(s,4H),2.73–2.46(m,16H),2.38(d,J＝22.4Hz,1H),1.88(d,J＝11.4Hz,2H),1.84–1.68(m,3H),1.60(dd,J＝27.8,14.4Hz,2H),1.52–1.41(m,6H),1.40–1.33(m,8H),1.26(dd,J＝12.3,6.6Hz,17H),1.16(d,J＝6.8Hz,5H),1.14–1.09(m,2H),1.03(d,J＝6.8Hz,3H),0.96(d,J＝6.6Hz,3H),0.92–0.71(m,6H),0.54(dt,J＝14.6,7.3Hz,3H).13C NMR(101MHz,CDCl3)δ216.18,203.91,169.64,157.21,151.26,140.28,133.57,132.25,130.29,127.82,126.99,125.84,123.32,103.12,82.22,79.36,78.08,77.50,69.84,68.61,66.19,60.30,51.16,49.76,47.49,44.86,42.50,40.25,39.38,39.05,31.39,29.75,29.63,22.06,20.94,19.70,18.29,15.84,14.63,14.34,13.94,9.94.HR-MS(ESI)(M+H)+m/z 794.4536,calcd for C44H63N3O10793.4513.
Example 2
(S2) preparation of 11, 12-dideoxy-3-O-descladinose-6-O-methyl-3-oxo-12, 11- (oxycarbonyl (quinoline-7-hydroxy-substituted propyl) imino) erythromycin
Synthetic route to compound S2:
Intermediate 6(0.71g, 1eq) and intermediate (b2, 4eq) were dissolved in 10mL of a mixed system of acetonitrile/water (9:1) and heated under reflux overnight. The reaction mixture was cooled to room temperature, diluted with dichloromethane, and washed with saturated brine 3 times. The organic phase was dried over anhydrous sodium sulfate, filtered and spin dried. The residue was separated by column chromatography to give the desired compound S2.1H NMR(400MHz,CDCl3)δ8.80(s,1H),8.06(t,J＝9.3Hz,1H),7.77–7.62(m,2H),7.56–7.33(m,1H),7.27–7.21(m,2H),7.16(dt,J＝15.0,7.5Hz,2H),4.98(dd,J＝19.3,10.2Hz,1H),4.36(t,J＝10.8Hz,1H),4.29(d,J＝6.7Hz,1H),4.27–4.20(m,2H),4.21–4.11(m,4H),4.07(d,J＝6.7Hz,1H),3.95–3.78(m,5H),3.70–3.52(m,4H),3.36(dd,J＝19.2,11.7Hz,1H),3.19–3.03(m,3H),2.94(dt,J＝29.6,19.6Hz,2H),2.81–2.68(m,4H),2.64(s,2H),2.54(d,J＝27.2Hz,9H),2.23(ddd,J＝19.4,17.5,8.9Hz,4H),2.08–1.82(m,5H),1.78(d,J＝13.2Hz,2H),1.74–1.52(m,6H),1.49(d,J＝18.6Hz,5H),1.42–1.32(m,10H),1.26(dd,J＝12.3,6.9Hz,3H),1.16(d,J＝6.8Hz,6H),1.03(d,J＝6.8Hz,6H),1.00–0.92(m,3H),0.91–0.72(m,3H).13C NMR(101MHz,CDCl3)δ215.94,203.84,169.66,160.07,157.08,150.28,135.72,130.87,128.77,128.62,123.47,120.12,118.77,107.78,103.05,82.24,79.28,78.03,77.20,71.74,69.80,68.57,66.23,65.76,65.51,60.52,51.14,49.75,47.36,44.84,41.27,40.24,39.29,38.97,31.86, 30.50,29.74,29.63,29.25,27.65,26.90,22.62,22.16,20.94,19.69,19.10,18.24,15.70,14.52,14.39,14.06,13.84,13.67,10.35.HR-MS(ESI)(M+H)+m/z 798.4502,calcd for C43H63N3O10797.4463.
Example 3
(S3) preparation of 11, 12-dideoxy-3-O-decladinose-6-O-methyl-3-oxo-12, 11- (oxycarbonyl (3- (6-methyl-quinolyl) -3(E) -butenyl) imino) erythromycin
Synthetic route to compound S3:
Intermediate 6(0.71g, 1eq) and intermediate (c3, 4eq) were dissolved in 10mL of a mixed system of acetonitrile/water (9:1) and heated under reflux overnight. The reaction mixture was cooled to room temperature, diluted with dichloromethane, and washed with saturated brine 3 times. Drying the organic phase with anhydrous sodium sulfate, filtering, and rotatingAnd (5) drying. The residue was separated by column chromatography to give the desired compound S3.1H NMR(400MHz,CDCl3)δ8.84(s,1H),7.97(s,1H),7.96–7.84(m,2H),7.60–7.50(m,2H),7.46(t,J＝10.8Hz,2H),6.71(d,J＝16.0Hz,1H),6.40(dt,J＝28.4,10.0Hz,1H),5.09–4.87(m,2H),4.40–4.13(m,5H),3.93–3.74(m,6H),3.62(dd,J＝16.2,7.3Hz,2H),3.59–3.42(m,4H),3.32–3.19(m,2H),3.18–2.98(m,5H),2.93(dd,J＝17.1,8.0Hz,1H),2.73(s,3H),2.62(dd,J＝26.6,8.7Hz,7H),2.50(d,J＝3.5Hz,7H),2.48–2.41(m,2H),2.38(s,10H),2.25(d,J＝10.3Hz,1H),2.07–1.87(m,2H),1.78(dd,J＝26.6,12.3Hz,6H),1.68– 1.50(m,4H),1.49–1.41(m,7H),1.41–1.33(m,9H),1.33–1.20(m,23H),1.14(dd,J＝18.9,11.3Hz,7H),1.10–1.04(m,2H),1.01(t,J＝5.9Hz,6H),0.95–0.75(m,6H),0.57(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3)δ216.26,203.94,169.61,157.17,148.80,145.78,136.43,131.17,131.08,130.33,129.75,128.94,128.63,128.08,126.89,126.62,103.55,82.26,82.17,79.40,78.12,77.60,77.21,70.09,69.16,66.00,60.46,51.22,49.83,47.62,47.44,44.88,42.57,40.20,39.50,39.09,31.32,29.63,28.78,22.12,21.53,21.05,19.69,18.32,15.94,15.74,14.68,14.29,14.08,13.95,10.32,10.04.HR-MS(ESI)(M+H)+m/z 808.4702,calcd for C45H65N3O10807.4670.
example 4
(S4) preparation of 11, 12-dideoxy-3-O-decladinose-6-O-methyl-3-oxo-12, 11- (oxycarbonyl (3- (6-methoxy-quinolyl) -3(E) -butenyl) imino) erythromycin
Synthetic route to compound S4:
Intermediate 6(0.71g, 1eq) and intermediate (d3,4eq) were dissolved in 10mL of a mixed system of acetonitrile/water (9:1) and heated under reflux overnight. Cooling the reaction liquid to room temperature, adding dichloromethane to diluteThe reaction solution was discharged, followed by washing with saturated brine 3 times. The organic phase was dried over anhydrous sodium sulfate, filtered and spin dried. The residue was separated by column chromatography to give the desired compound S4.1H NMR(400MHz,CDCl3)δ8.74(s,1H),7.99(s,1H),7.91(d,J＝9.1Hz,1H),7.03(d,J＝2.2Hz,1H),6.70(d,J＝15.9Hz,1H),6.49–6.36(m,1H),4.98(d,J＝10.3Hz,1H),4.33(d,J＝7.2Hz,1H),4.26(t,J＝11.5Hz,1H),3.91(d,J＝6.3Hz,5H),3.83(dd,J＝12.1,5.3Hz,5H),3.68–3.51(m,3H),3.34(dd,J＝9.7,7.5Hz,1H),3.19–3.02(m,2H),2.87(dd,J＝17.6,8.4Hz,1H),2.74(d,J＝14.5Hz,3H),2.60(t,J＝17.0Hz,4H),2.55–2.41(m,7H),1.77(dt,J＝14.8,9.4Hz,3H),1.60(dd,J＝28.2,15.2Hz,1H),1.51–1.40(m,4H),1.40–1.31(m,7H),1.26(dd,J＝14.0,7.7Hz,10H),1.15(t,J＝7.6Hz,4H),1.01(d,J＝6.8Hz,3H),0.56(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3)δ216.25,203.96,169.61,157.80,157.20,147.27,143.25,130.63,130.27,130.01,129.11,128.88,121.59,105.14,103.23,82.19,79.34,78.09,77.63,77.20,69.90,68.76,66.13,60.49,55.46,51.21,49.81,47.56,44.86,42.55,40.20,39.44,39.10,31.34,29.62,29.44,22.11,20.97,19.68,18.29,15.95,14.68,14.31,13.95,10.00.HR-MS(ESI)(M+H)+m/z 824.4630,calcd for C45H65N3O11823.4619.
Example 5
(S5) preparation of 11, 12-dideoxy-3-O-decladinose-6-O-methyl-3-oxo-12, 11- (oxycarbonyl (3- (6-benzyloxy-quinolyl) -3(E) -butenyl) imino) erythromycin
Synthetic route to compound S5:
Intermediate 6(0.71g, 1eq) and intermediate (e3,4eq) were dissolved in 10mL of a mixed system of acetonitrile/water (9:1) and heated under reflux overnight. Cooling the reaction solution to room temperature, adding dichloromethane to dilute the reaction solution, and then diluting the reaction solution with waterWashed with brine 3 times. The organic phase was dried over anhydrous sodium sulfate, filtered and spin dried. The residue was separated by column chromatography to give the desired compound S5.1H NMR(400MHz,CDCl3)δ8.76(s,1H),8.02–7.89(m,2H),7.55–7.44(m,3H),7.40(t,J＝7.4Hz,3H),7.35(dt,J＝14.5,5.4Hz,3H),7.12(d,J＝2.5Hz,1H),6.75–6.66(m,1H),6.41(dt,J＝13.3,7.0Hz,1H),5.22–5.12(m,3H),4.98(d,J＝8.8Hz,1H),4.38(t,J＝10.0Hz,1H),4.26(t,J＝10.2Hz,2H),3.92–3.76(m,5H),3.68–3.50(m,3H),3.41(dd,J＝9.8,7.4Hz,1H),3.19–2.96(m,4H),2.76(d,J＝20.3Hz,3H),2.60(d,J＝11.4Hz,11H),2.03(d,J＝6.2Hz,1H),1.90(d,J＝10.6Hz,1H),1.85–1.72(m,2H),1.61(dd,J＝26.8,13.1Hz,2H),1.51–1.43(m,5H),1.35(dd,J＝17.0,8.5Hz,8H),1.30–1.22(m,12H),1.16(t,J＝7.7Hz,5H),1.08(d,J＝6.8Hz,1H),1.02(d,J＝6.8Hz,4H),0.91–0.77(m,2H),0.57(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3)δ216.26,203.99,169.62,157.21,156.96,147.37,143.29,136.48,130.74,130.65,130.36,130.05,129.08,128.87,128.62,128.09,127.70,127.53,121.96,106.52,102.98,82.20,79.29,78.08,77.68,77.20,70.20,69.74,68.44,66.30,60.50,51.22,49.82,47.51,44.87,42.55,40.21,39.40,39.12,31.35,29.94,29.64,22.13,20.92,19.69,18.30,15.94,14.72,14.35,13.97,10.40,10.03.HR-MS(ESI)(M+H)+m/z 900.4957,calcd for C51H69N3O11899.4932.
Example 6
(S6) preparation of 11, 12-dideoxy-3-O-decladinose-6-O-methyl-3-oxo-12, 11- (oxycarbonyl (3- (6-phenyl-quinolyl) -3(E) -butenyl) imino) erythromycin
Synthetic route to compound S6:
Intermediate 6(0.71g, 1eq) and intermediate (f3,4eq) were dissolved in 10mL of a mixed system of acetonitrile/water (9:1), and addedHot reflux overnight. The reaction mixture was cooled to room temperature, diluted with dichloromethane, and washed with saturated brine 3 times. The organic phase was dried over anhydrous sodium sulfate, filtered and spin dried. The residue was separated by column chromatography to give the desired compound S6.1H NMR(400MHz,CDCl3)δ8.92(s,1H),8.16–8.05(m,3H),8.03–7.94(m,2H),7.89(d,J＝8.6Hz,1H),7.71(d,J＝7.6Hz,3H),7.60(d,J＝7.5Hz,1H),7.47(dd,J＝15.5,8.1Hz,3H),7.38(t,J＝6.9Hz,2H),6.75(d,J＝15.9Hz,1H),6.57–6.40(m,1H),5.00(d,J＝10.2Hz,1H),4.31(d,J＝7.1Hz,1H),4.24(t,J＝11.2Hz,1H),3.98–3.81(m,3H),3.62(s,1H),3.61–3.50(m,2H),3.33–3.18(m,2H),3.19–3.01(m,3H),2.97–2.85(m,2H),2.75(s,3H),2.61(d,J＝4.2Hz,5H),2.39(d,J＝17.0Hz,7H),1.89–1.69(m,4H),1.62(dd,J＝27.2,11.9Hz,2H),1.45(s,5H),1.38(d,J＝8.8Hz,6H),1.30(d,J＝7.2Hz,7H),1.25(d,J＝5.3Hz,7H),1.17(d,J＝6.8Hz,4H),1.04(t,J＝8.6Hz,4H),0.59(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ216.28,203.93,169.65,157.20,149.70,146.56,140.37,139.35,131.94,130.76,130.25,129.42,128.88,128.80,128.54,128.27, 127.61,127.37,125.49,103.60,82.18,79.46,78.14,77.63,70.12,69.20,66.02,60.48,51.24,49.86,47.66,44.89,42.57,40.20,39.53,39.11,31.37,29.64,28.71,22.14,21.07,19.70,18.33,16.00,14.69,14.30,13.97,10.09.HR-MS(ESI)(M+H)+m/z 860.4933,calcd for C50H67N3O10859.4826.
Example 7(S7) preparation of 11, 12-dideoxy-3-O-decladinose-6-O-methyl-3-oxo-12, 11- (oxycarbonyl (3- (7-methyl-quinolyl) -3(E) -butenyl) imino) erythromycin
Synthetic route to compound S7:
Intermediate 6(0.71g, 1eq) and intermediate (f3,4eq) were dissolved in 10mL of a mixture of acetonitrile/water (9:1)In the series, the mixture was heated under reflux overnight. The reaction mixture was cooled to room temperature, diluted with dichloromethane, and washed with saturated brine 3 times. The organic phase was dried over anhydrous sodium sulfate, filtered and spin dried. The residue was separated by column chromatography to give the desired compound S7.1H NMR(400MHz,CDCl3)δ8.87(s,1H),8.02(s,1H),7.78(dd,J＝14.7,7.0Hz,2H),7.72–7.61(m,2H),7.31(d,J＝8.0Hz,2H),6.70(d,J＝16.0Hz,1H),6.48–6.33(m,1H),4.95(dd,J＝21.4,9.7Hz,2H),4.31(t,J＝6.2Hz,1H),4.22(dt,J＝16.4,7.0Hz,3H),3.92–3.79(m,5H),3.64–3.44(m,6H),3.34–3.22(m,2H),3.17–3.01(m,4H),2.71(d,J＝13.8Hz,5H),2.58(d,J＝9.4 Hz,5H),2.51(dd,J＝15.4,6.5Hz,8H),2.43(s,11H),1.78(dd,J＝19.9,12.1Hz,5H),1.64–1.52(m,3H),1.44(d,J＝4.7Hz,6H),1.35(dd,J＝11.5,7.2Hz,9H),1.26(dd,J＝13.8,6.9Hz,21H),1.15(t,J＝7.6Hz,6H),1.01(d,J＝6.8Hz,5H),0.84(dtd,J＝21.1,13.9,7.2Hz,4H),0.57(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3)δ216.24,203.95,169.59,157.18,149.63,147.36,139.06,131.74,131.54,129.60,129.41,128.90,127.99,127.88,127.43,127.16,126.06,103.40,82.16,79.36,78.10,77.62,70.02,68.99,66.06,60.78,60.45,51.21,49.83,47.58,47.42,44.86,42.58,40.22,39.47,39.09,31.29,29.62,29.07,22.12,21.81,21.01,19.68,18.31,15.94,15.73,14.69,14.30,14.07,13.95,10.34,10.02.HR-MS(ESI)(M+H)+m/z 808.4695,calcd for C45H65N3O10807.4670.
Example 8
(S8) preparation of 11, 12-dideoxy-3-O-decladinose-6-O-methyl-3-oxo-12, 11- (oxycarbonyl (3- (7-methoxy-quinolyl) -3(E) -butenyl) imino) erythromycin
Synthetic route to compound S8:
Intermediate 6(0.71g, 1eq) and intermediate (h)3,4eq) was dissolved in 10mL of a mixed system of acetonitrile/water (9:1), and the mixture was refluxed overnight. The reaction mixture was cooled to room temperature, diluted with dichloromethane, and washed with saturated brine 3 times. The organic phase was dried over anhydrous sodium sulfate, filtered and spin dried. The residue was separated by column chromatography to give the desired compound S8.1H NMR(400MHz,CDCl3)δ8.84(s,1H),8.02(s,1H),7.64(t,J＝7.9Hz,2H),7.37(d,J＝7.3Hz,3H),7.21–7.11(m,3H),6.70(d,J＝16.0Hz,1H),6.44–6.30(m,1H),5.03–4.90(m,2H),4.35–4.17(m,4H),3.93(d,J＝3.8Hz,8H),3.90–3.79(m,5H),3.66–3.45(m,6H),3.29–3.17(m,3H),3.09(ddd,J＝20.5,13.3,5.4Hz,6H),2.76(d,J＝13.3Hz,3H),2.66–2.54(m,7H),2.48(d,J＝23.2Hz,2H),2.34(d,J＝12.8Hz,12H),1.88–1.54(m,11H),1.47(dd,J＝13.4,8.2Hz,7H),1.41–1.33(m,10H),1.29(ddd,J＝17.4,14.5,7.3Hz,31H),1.16(t,J＝7.6Hz,8H),1.11–1.06(m,2H),1.02(t,J＝6.1Hz,6H),0.93–0.77(m,8H),0.58(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3)δ216.27,203.96,169.61,160.27,157.20,149.89,148.81,131.59,128.88,128.83,128.77,128.52,123.25,119.80,107.13,103.72,82.34,82.16,79.47,78.14,77.65,70.21,69.37,65.96,60.48,55.44,51.25,49.87,47.68,47.51,44.90,42.64,40.21,39.56,39.13,31.30,29.66,29.28,28.46,22.65,22.15,21.11,19.71,18.36,15.98,15.78,14.72,14.29,14.09,13.98,10.04.HR-MS(ESI)(M+H)+m/z 900.4963,calcd for C51H69N3O11899.4932.
Example 9
(S9) preparation of 11, 12-dideoxy-3-O-decladinose-6-O-methyl-3-oxo-12, 11- (oxycarbonyl (3- (7-benzyloxy-quinolyl) -3(E) -butenyl) imino) erythromycin
Synthetic route to compound S9:
Intermediate 6(0.71g, 1eq)And intermediate (i3, 4eq) were dissolved in 10mL of a mixed system of acetonitrile/water (9:1), and the mixture was refluxed overnight. The reaction mixture was cooled to room temperature, diluted with dichloromethane, and washed with saturated brine 3 times. The organic phase was dried over anhydrous sodium sulfate, filtered and spin dried. The residue was separated by column chromatography to give the desired compound S9.1H NMR(400MHz,CDCl3)δ8.84(s,1H),8.02(s,1H),7.66(t,J＝7.4Hz,2H),7.47(t,J＝6.9Hz,6H),7.39(t,J＝7.3Hz,3H),7.36–7.29(m,2H),7.23(d,J＝8.8Hz,1H),6.69(d,J＝15.9Hz,1H),6.44–6.30(m,1H),5.18(s,3H),4.99(d,J＝9.8Hz,2H),4.39–4.32(m,1H),4.29–4.17(m,3H),3.92–3.80(m,4H),3.66–3.54(m,4H),3.40–3.28(m,1H),3.22(d,J＝5.8Hz,1H),3.18–2.99(m,4H),2.90(d,J＝12.1Hz,2H),2.79–2.67(m,4H),2.59(dd,J＝15.4,6.4Hz,5H),2.54(d,J＝12.2Hz,9H),1.81(dt,J＝18.0,11.3Hz,4H),1.65–1.55(m,3H),1.45(s,6H),1.41–1.33(m,9H),1.27(dd,J＝13.2,6.9Hz,24H),1.15(dd,J＝16.9,9.1Hz,8H),1.02(d,J＝6.6Hz,6H),0.93–0.75(m,8H),0.58(t,J＝7.1Hz,4H).13C NMR(101MHz,CDCl3)δ216.25,203.99,169.60,159.38,157.19,149.83,148.64,136.39,131.63,128.90,128.59,128.09,127.69,123.38,120.16,108.27,103.18,82.17,79.31,78.09,77.67,70.13,69.86,68.72,66.18,60.49,51.22,49.83,47.54,44.88,42.62,40.20,39.43,39.12,31.28,29.64,29.46,29.26,22.63,22.14,20.97,19.69,18.31,15.94,14.72,14.33,14.07,13.96,10.35,10.05.HR-MS(ESI)(M+H)+m/z 836.4722,calcd for C46H65N3O11835.4619.
Example 10
(S10) preparation of 11, 12-dideoxy-2-fluoro-3-O-decladinose-6-O-methyl-3-oxo-12, 11- (oxycarbonyl (3-quinolyl-3 (E) -butenyl) imino) erythromycin
Synthetic route to compound S10:
The starting material (1.0mmol) was dissolved in 10mL of pyridine, acetic anhydride (2.0mmol) was added dropwise under cooling in an ice-water bath, and after completion of the addition, the reaction mixture was gradually returned to room temperature and stirred overnight. Pyridine was distilled off under reduced pressure, and the residue was isolated by column chromatography to give intermediate j 1.
dissolving intermediate j1(1.0mmol) in tetrahydrofuran, adding sodium hydride (1.5mmol) under the condition of ice-water bath, stirring for 0.5h, adding NISF (1.2mmol), stirring at low temperature for 2h, adding saturated saline solution to quench the reaction, extracting the reaction solution with ethyl acetate for three times, combining organic phases, drying with anhydrous sodium sulfate, filtering, spin-drying, and separating the residue by column chromatography to obtain intermediate j 2.
J2(1.0mmol) was dissolved in 10mL of methanol, heated to reflux overnight, and the reaction was monitored by dot plate. The reaction system is cooled to room temperature and is dried in a spinning mode to obtain the target product S10.
1H NMR(400MHz,CDCl3):δ8.94(s,1H),8.03～8.08(m,2H),7.78(d,1H,J＝8.0Hz),7.63(t,1H,J＝8.0Hz),7.51(t,1H,J＝8.0Hz),6.75(d,1H,J＝16.0Hz),6.48(m,1H),5.00(d,1H,J＝10.0Hz),4.31(d,1H,J＝7.2Hz),4.26(d,1H,J＝8.0Hz),3.86(m,3H),3.72(s,1H),3.63(s,1H),3.54(m,2H),3.22(m,2H), 3.63(s,1H),3.14(m,3H),2.75(s,3H),2.61(m,3H),2.47(m,2H),2.32(s,6H),1.87(s,1H),1.79(d,1H,J＝21.0)1.82～1.77(m,2H),1.68～1.62(m,2H),1.46(s,3H),1.38(s,3H),1.26～1.25(m,6H),1.21(m,6H),1.18(d,3H,J＝7.2Hz),1.04(d,3H,J＝6.8Hz),0.94(m,3H),0.59(d,3H,J＝7.2Hz).13C NMR(101MHz,CDCl3)δ216.57,202.67,166.17,157.00,151.81,134.65,131.65,128.92,128.57,127.75,127.50,126.90,126.61,126.37,104.04,82.10,80.62,78.40,78.33,70.23,69.42,65.72,60.97,49.35,48.99,44.56,44.51,40.69,40.14,39.56,39.16,35.68,31.30,29.55,28.22,22.06,21.05,21.01,19.59,17.82,14.62,13.91,10.33.HR-MS(ESI)(M+H)+m/z 812.4506,calcd for C44H62FN3O10811.4419.
Example 11
(S11) preparation of 11, 12-dideoxy-2-fluoro-3-O-descladinose-6-O-methyl-3-oxo-12, 11- (oxycarbonyl (quinoline-3-hydroxy-substituted propyl) imino) erythromycin
Synthetic route to compound S11:
the starting material (1.0mmol) was dissolved in 10mL of pyridine, acetic anhydride (2.0mmol) was added dropwise under cooling in an ice-water bath, and after completion of the addition, the reaction mixture was gradually returned to room temperature and stirred overnight. Pyridine was distilled off under reduced pressure, and the residue was isolated by column chromatography to give intermediate k 1.
Dissolving intermediate k1(1.0mmol) in tetrahydrofuran, adding sodium hydride (1.5mmol) under the condition of ice-water bath, stirring for 0.5h, adding NISF (1.2mmol), stirring at low temperature for 2h, adding saturated saline solution to quench the reaction, extracting the reaction solution with ethyl acetate for three times, combining organic phases, drying with anhydrous sodium sulfate, filtering, spin-drying, and separating the residue by column chromatography to obtain intermediate k 2.
K2(1.0mmol) was dissolved in 10mL of methanol, heated to reflux overnight, and the reaction was monitored by dot-panel. The reaction system is cooled to room temperature and is dried in a spinning mode to obtain the target product S11.1H NMR(400MHz,CDCl3)δ8.64(d,J＝2.7Hz,1H),8.02(d,J＝8.1Hz,1H),7.72(d,J＝7.6Hz,1H),7.51(dt,J＝14.7,6.9Hz,2H),7.38(d,J＝2.5Hz,1H),4.93(d,J＝9.3Hz,1H),4.31(d,J＝7.2Hz,1H),4.10(dd,J＝26.1,7.9Hz,3H),3.91(dd,J＝17.0,11.3Hz,1H),3.86–3.73(m,1H),3.63–3.46(m,3H),3.21(dd,J＝10.0,7.4Hz,1H),3.20–3.08(m,1H),2.62(s,4H),2.58–2.43(m,2H),2.31(s,5H),2.27–2.13(m,2H),2.12–1.94(m,2H),1.88(d,J＝12.1Hz,1H),1.78(d,J＝21.4Hz,2H),1.75–1.58(m,3H),1.58–1.46(m,3H),1.35(s,3H),1.30(d,J＝7.0Hz,3H),1.24(t,J＝6.7Hz,6H),1.18(d,J＝6.8Hz,3H),1.04(d,J＝6.9Hz,3H),0.86(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3)δ216.46,202.93,202.73,166.51,166.30,157.15,152.36,144.85,143.45,129.04,128.87,126.91,126.72,126.51,112.92,104.07,82.17,80.61,78.55,78.36,77.20,70.28,69.48,66.00,65.88,61.14,49.25,44.62,41.36,40.80,40.22,39.55,39.19,29.66,28.39,26.92,25.12,22.10,21.14,19.71,17.86,15.02,14.61,13.75,10.39.HR-MS(ESI)(M+H)+m/z 816.4533,calcd for C43H62FN3O11815.4368.
Experimental examples section
experimental example 1 pharmacological experiment: in vitro antibacterial Activity test
The invention provides the application of the compound in the aspect of antibiosis by utilizing the in-vitro antibacterial activity experiment.
(1) The test method comprises the following steps: culture medium and incubation conditions
Incubating staphylococcus and Moraxella catarrhalis in CAMHB medium at 35 deg.C for 16-20 h; incubating Streptococcus in CAMHB culture medium containing 5% horse serum at 35 deg.C for 20-24 hr; haemophilus was incubated in HTM broth for 20-24h at 35 ℃.
minimum Inhibitory Concentration (MIC) determination
Standard two-fold broth dilution was used. The concentration range of the antibacterial drug is 64-0.004 mg/L. The final concentration of the tested bacterial liquid is about 1 multiplied by 105CFU/ml。
(2) Control drug: clarithromycin (Cla), telithromycin (Teli)
Clinical isolate 11 strains:
Methicillin-sensitive, erythromycin-sensitive Staphylococcus aureus-ATCC 29213
methicillin-resistant and erythromycin-resistant staphylococcus aureus-ATCC 33591
Methicillin-sensitive, erythromycin-sensitive Staphylococcus epidermidis ATCC12228
Methicillin-resistant and erythromycin-resistant staphylococcus epidermidis-13-3
Erythromycin sensitive streptococcus pyogenes-11-8
Erythromycin drug-resistant streptococcus pyogenes-12-1
Clarithromycin-sensitive Moraxella catarrhalis-12-1
Clarithromycin-resistant Moraxella catarrhalis-12-2
Escherichia coli ATCC25922
Klebsiella pneumoniae-ATCC 700603
pseudomonas aeruginosa-ATCC 27835
TABLE 1 MIC results (mg/L) for 11 strains of bacteria for Compounds S1-S11 and controls
Experiments prove that the compound sample with the structural formula of S1-S11, prepared by the method, has broad spectrum and simultaneously inhibits outstanding antibacterial activity and drug-resistant activity of gram-positive bacteria and gram-negative bacteria.
The foregoing description is of the preferred embodiments of the present invention only, and thus all features and methods that are described in the claims of the present invention are included in the claims of the present invention.
Claims (6)
1. Erythromycin A antibiotic derivatives and pharmaceutically acceptable salts thereof, wherein the derivatives are selected from the following:
(S1)11, 12-dideoxy-3-O-decladinose-6-O-methyl-3-oxo-12, 11- (oxycarbonyl (4-isoquinolinyl-3 (E) -butenyl) imino) erythromycin
(S2)11, 12-dideoxy-3-O-descladinose-6-O-methyl-3-oxo-12, 11- (oxycarbonyl (quinoline-7-hydroxy substituted propyl) imino) erythromycin
(S10)11, 12-dideoxy-2-fluoro-3-O-decladinose-6-O-methyl-3-oxo-12, 11- (oxycarbonyl (3-quinolyl-3 (E) -butenyl) imino) erythromycin
(S11)11, 12-dideoxy-2-fluoro-3-O-descladinose-6-O-methyl-3-oxo-12, 11- (oxycarbonyl (quinoline-3-hydroxy-substituted propyl) imino) erythromycin
2. a process for the preparation of erythromycin a-type antibiotic derivatives according to claim 1, characterized by comprising the steps of:
Addition reaction of macrolide intermediate compound 6 with a primary amine side chain containing a quinoline ring; or 2 '-hydroxyl is protected, substituted at 2-position of large ring and then 2' -hydroxyl protecting group is removed,
The method comprises the following steps:
(1) Introducing substituted quinoline ring-substituted carbamate functional group into 11, 12-positions of the raw material 6 to obtain the corresponding substituted erythromycin A quinoline ring side chain ketolide derivative,
(2) Protecting the 2' -position of the ketolide derivative, then substituting the 2-position and then deprotecting to obtain the corresponding 2-position substituted erythromycin A quinoline ring side chain ketolide derivative.
3. A pharmaceutical composition comprising at least one erythromycin a class antibiotic derivative of claim 1 and a pharmaceutically acceptable carrier.
4. use of an erythromycin A derivative as claimed in claim 1, for the preparation of a medicament for inhibiting bacteria.
5. Use according to claim 4, wherein said bacteria are selected from the group consisting of gram-positive bacteria, gram-negative bacteria and other pathogens.
6. The use according to claim 5, wherein said gram-positive bacteria are selected from the group consisting of staphylococci, Streptococcus pyogenes, Staphylococcus epidermidis;
the gram-negative bacteria are selected from Moraxella catarrhalis, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa;
The other pathogen is selected from Streptococcus pneumoniae, Rickettsia, Haemophilus influenzae, Mycoplasma pneumoniae, Chlamydia, Roman pathogen, bird blood plasma, Toxoplasma, Mycobacterium, Listeria monocytogenes, meningococcus.
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| CN1151746A (en) * | 1994-05-03 | 1997-06-11 | 鲁索-艾克勒夫公司 | Novel erythromycin derivatives, method for their preparation and their use as drugs |
| WO1999021870A1 (en) * | 1997-10-29 | 1999-05-06 | Taisho Pharmaceutical Co., Ltd. | Erythromycin a 11, 12-carbamate derivatives |
| WO2006080954A1 (en) * | 2004-07-28 | 2006-08-03 | Ranbaxy Laboratories Limited | Ketolide derivatives as antibacterial agents |
| CN1865274A (en) * | 2006-06-19 | 2006-11-22 | 中国医学科学院药物研究所 | Macrolide medicine double-side-chain erythromycin A derivative, synthesis method and application |
| CN102417530A (en) * | 2010-09-26 | 2012-04-18 | 中国医学科学院药物研究所 | Synthesis method of broad spectrum antibiotics erythromycin A macrocyclic ketolide derivatives and application |
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| CN1151746A (en) * | 1994-05-03 | 1997-06-11 | 鲁索-艾克勒夫公司 | Novel erythromycin derivatives, method for their preparation and their use as drugs |
| WO1999021870A1 (en) * | 1997-10-29 | 1999-05-06 | Taisho Pharmaceutical Co., Ltd. | Erythromycin a 11, 12-carbamate derivatives |
| WO2006080954A1 (en) * | 2004-07-28 | 2006-08-03 | Ranbaxy Laboratories Limited | Ketolide derivatives as antibacterial agents |
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